The recent tragic nuclear power plant accidents in Japan caused severe leaks of radioactive Iodine-131 and Cesium-137 and widespread exposure scare of radiation. In addition, the global use and storage of radioactivity is increasing rapidly. Millions of radioactive sealed sources are used around the world for legitimate and beneficial commercial applications such as cancer treatment, food and blood sterilization, oil exploration, remote electricity generation, radiography, and scientific research. These applications use isotopes such as Cesium-137, Cobalt-60, Strontium-90, Americium-241, Iridium-192, Plutonium-238, Plutonium-239, Curium-244, Radium-226, and Californium-252. Many of these radiological sources at sites around the world are no longer needed and have been abandoned or orphaned; others are poorly guarded, making the risk of theft or sabotage significant. Currently, there are tens of thousands of civilian locations worldwide with radioactive material, about 5,000 of which contain sources of 1,000 curies or greater (Office of Global Threat Reduction (NA-21). GTRI Strategic Plan, release date January 2007. 955 L'Enfant Plaza, Washington, D.C. 20585. Biopulos, loanna et al. The Office of Global Threat Reduction: reducing the global threat from radiological dispersal devices. 2007. JNMM Volume 35 Issue 3 PP 36-40). Beyond the public safety concerns are the clinical implications of radiation use.
Outside the radiation therapy clinic there is also significant relevance to identifying and characterizing novel compounds that protect cells from radiation induced cell death. Fundamental to radiation exposure and injury is DNA strand breaks, resulting in genetic instability and DNA deletions which are involved in cell death, cellular dysfunction, as well as long-term consequences such as birth defects and cancer.
There are currently only 5 agents approved by the FDA for radiation protection, and none are approved for non clinical use. However, out of these, only one agent is classified as a cytoprotectant (Amifostine™), and this agent, along with current leads, have demonstrated poor toxicity profiles (see, e.g., Seed, T. M., Health Phys, 2005. 89(5): p. 531-45; Brizel, D. M J Clin Oncol, 2007. 25(26): p. 4084-9), which is a common shortcoming with all current small molecule leads in this area. The other agents are Potassium Iodide, Zn-DTPA (Trisodium zinc diethylenetriaminepentaacetate) and Prussian Blue Ferric III/hexacyanoferrate II as chelators used for isotope exposure, and Granisetron™ as an anti-emetic.
Thus, there is a need for novel drugs used for the prophylaxis, mitigation and treatment of radiation injury.
The embodiments described below address the above mentioned problems and needs.